The tobacco industry has added a wide range of chemicals to cigarettes to increase product stability and modify taste and sensory qualities of smoke. While the Family Smoking Prevention and Tobacco Control Act outlawed tobacco flavor additives, menthol was exempt from regulation. Mentholated cigarettes are especially popular with beginning smokers and in minority populations disproportionally affected by COPD, lung cancer and hypertension. Recently, electronic cigarettes, marketed as non-toxic nicotine delivery devices, have become popular tobacco cigarette substitutes. Electronic cigarettes contain large amounts of the same chemical flavor and sensory additives outlawed for use in tobacco cigarettes, including irritating terpenes such as linalool. Our research has shown that menthol, at levels similar or below in smoke of mentholated cigarettes, strongly inhibited the respiratory irritation response to tobacco smoke irritants in mice. Aerosols from electronic cigarettes elicited strong irritation responses in mice, comparable to responses elicited by tobacco cigarette smoke. Physiological experiments showed that menthol and linalool are potent modulators of TRPM8 and TRPA1, two chemosensory ion channels expressed in sensory neurons innervating the respiratory system. We hypothesize that: 1.) Menthol acts as a counterirritant, blocking sensory neuronal responses to inhaled noxious chemicals through interaction with TRPA1 or TRPM8, 2) As a tobacco additive, menthol facilitates smoke inhalation through inhibition of neuronal irritant receptor signalling, thereby accelerating nicotie dependence and lung disease and , 3) the high amounts of chemical additives in electronic cigarettes are added to mimic the sensory impact of tobacco smoke and may cause chronic irritation and inflammatory responses. The studies proposed in this application will use physiological, biochemical, molecular and behavioral approaches to: Aim 1.) Define the roles of TRPA1 and TRPM8 in menthol-induced inhibition of acute respiratory irritation. Aim 2.) Examine the pharmacological effects of menthol and menthol-related compounds on irritant-induced activation of sensory neurons. Aim 3.) Determine the effects of menthol inhalation on smoking-induced lung inflammation and emphysema. Aim 4.) Investigate the sensory and inflammatory effects of electronic cigarette aerosols and their chemical additives. Our proposed research will provide new insights into neuronal mechanisms of airway irritation and remodeling, and define a scientific basis for regulatory efforts targeting menthol and other additives to tobacco and electronic cigarettes. PUBLIC HEALTH RELEVANCE: Relevance As an additive to cigarettes, menthol is suspected to accelerate and maintain nicotine dependence and to increase the toxicity of tobacco smoke. Electronic cigarettes, rapidly gaining market share as supposedly non-toxic nicotine delivery devices, also contain flavor additives and other chemicals with unknown health effects. Our research aims to reveal how cigarette additives affect the function of the respiratory system and, potentially, promote addiction and lung disease in smokers.